Bioerodible magnesium alloy microstructures for endoprostheses

ABSTRACT

A bioerodible endoprosthesis includes a bioerodible magnesium alloy including between 50 weight percent and 92 weight percent magnesium, at least 5.5 weight percent in sum of one or more elements selected from the group consisting of Ho, Er, Lu, Tb and Tm, and at least 2.0 weight percent in sum of one or more elements selected from the group consisting of Y, Nd and Gd. The bioerodible magnesium alloy has a microstructure including equiaxed Mg-rich solid solution-phase grains having an average grain diameter of less than or equal to 15 microns and second-phase precipitates and/or ceramic nanoparticles in grain boundaries between the equiaxed Mg-rich solid solution-phase grains. The secondary-phase precipitates or ceramic nanoparticles have an average longest dimension of 2.0 micron or less. The microstructure can be produced by one or more equal-channel high-strain processes.

TECHNICAL FIELD

This disclosure relates to microstructures for bioerodible magnesiumalloys used in endoprostheses and methods of producing thosemicrostructures.

BACKGROUND

Endoprostheses can be used to replace a missing biological structure,support a damaged biological structure, and/or enhance an existingbiological structure. Frequently, only a temporary presence of theendoprosthesis in the body is necessary to fulfill the medical purpose.Surgical intervention to remove endoprostheses, however, can causecomplications and may not even be possible. One approach for avoiding apermanent presence of all or part of an endoprosthesis is to form all orpart of the endoprosthesis out of bioerodible material. The term“bioerodible” as used herein is understood as the sum of microbialprocedures or processes solely caused by the presence of endoprosthesiswithin a body, which results in a gradual erosion of the structureformed of the bioerodible material.

At a specific time, the endoprosthesis, or at least the part of theendoprosthesis that includes the bioerodible material, loses itsmechanical integrity. The erosion products are mainly absorbed by thebody, although small residues can remain under certain conditions. Avariety of different bioerodible polymers (both natural and synthetic)and bioerodible metals (particularly magnesium and iron) have beendeveloped and are under consideration as candidate materials forparticular types of endoprostheses. Many of these bioerodible materials,however, have significant drawbacks. These drawbacks include the erosionproducts, both in type and in rate of release, as well as the mechanicalproperties of the material.

SUMMARY

A bioerodible endoprosthesis provided herein includes a bioerodiblemagnesium alloy including between 50 weight percent and 92 weightpercent magnesium, a total content of at least 5.5 weight percent of Ho,Er, Lu, Tb, and Tm in sum, and a total content of at least 2 weightpercent of Y, Nd, and Gd in sum. The bioerodible magnesium alloy isformed such that it has a microstructure defined by equiaxed Mg-richsolid solution-phase grains (i.e., alpha-phase grains) having an averagegrain diameter of less than or equal to 15 microns. In some cases,secondary phase precipitates can be located in grain boundaries betweenthe equiaxed Mg-rich solid solution-phase grains. In some cases, theceramic nanoparticles can be located in grain boundaries between theequiaxed Mg-rich solid solution-phase grains. In some cases, thesecondary phase precipitates and/or ceramic nanoparticles can have anaverage longest dimension of 500 nanometers or less. Bioerodiblemagnesium alloys having the microstructures provided herein can haveimproved mechanical properties suitable for endoprostheses, such asstents.

A method of processing a bioerodible magnesium alloy for endoprosthesesprovided herein can include the steps of forming an ingot or billet ofmolten magnesium alloy and performing at least one high-strain processon the ingot or billet to form the grain morphology provided herein. Insome cases, the processing can include holding the ingot or billet at atemperature above the solvus temperature (e.g., between 400° C. and 450°C.) for at least 2 hours to homogenize the ingot or billet prior toperforming the at least one high-strain process. The at least onehigh-strain process can be an equal-channel high-strain process and canbe conducted at a temperature of less than the solvus temperature (e.g.,a temperature below 400° C.). In some cases, multiple equal-channelhigh-strain processes are conducted using subsequently lowertemperatures.

A bioerodible magnesium alloy formulation can include magnesium and aplurality of rare earth metals. In some cases, the rare earth metals caninclude scandium (Sc), yttrium (Y), lanthanum (La), neodymium (Nd),gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium(Er), thulium (Tm), and/or lutetium (Lu). In some cases, the bioerodiblemagnesium alloy can include zirconium (Zr), calcium (Ca), zinc (Zn),and/or indium (In). In some cases, a bioerodible magnesium alloyprovided herein can include at least 5.5 weight percent in sum of one ormore elements selected from the group consisting of selected from thegroup consisting of Ho, Er, Lu, Tb and Tm. In some cases, a bioerodiblemagnesium alloy provided herein can include at least 2.0 weight percentin sum of one or more elements selected from the group consisting ofselected from the group consisting of Y, Nd and Gd. In some cases, abioerodible magnesium alloy provided herein can include aluminum, zinc,calcium, manganese, tin, neodymium, yttrium, cerium, lanthanum,gadolinium, or a combination thereof. In some cases, a bioerodiblemagnesium alloy provided here in can consist of:

-   -   Y: 0-10.0 weight percent;    -   Nd: 0-4.5 weight percent;    -   Gd: 0-9.0 weight percent;    -   Dy: 0-8.0 weight percent;    -   Ho: 0-19.0 weight percent;    -   Er: 0-23.0 weight percent;    -   Lu: 0-25.0 weight percent;    -   Tm: 0-21.0 weight percent;    -   Tb: 0-21.0 weight percent;    -   Zr: 0.1-1.5 weight percent;    -   Ca: 0-2.0 weight percent;    -   Zn: 0-1.5 weight percent;    -   In: 0-12.0 weight percent;    -   Sc: 0-15.0 weight percent;    -   incidental impurities up to a total of 0.3 weight percent; and    -   the balance being magnesium and under the condition that a total        content of Ho, Er, Lu, Tb and Tm is more than 5.5 weight        percent; a total content of Y, Nd and Gd is more than 2.0 weight        percent; and a total content of all alloy compounds except        magnesium is more than 8.5 weight percent. In some cases, a        bioerodible magnesium alloy provided herein includes between 70        weigh percent and 91.5 weight percent magnesium.

In some cases, ceramic nanoparticles can be added to the alloy. Ceramicnanoparticles provided herein can include any suitable ceramic material.In some cases, the ceramic nanoparticles can be insoluble in thebioerodible magnesium alloy. In some cases, ceramic nanoparticles caninclude one or more of the following ceramic materials: TiC, TiO₂ Si₃N₄,AlN, Al₂O₃, CeO₂, Boron Nitride, B₄C, and Y₂O₃.

Endorprostheses provided herein can have any suitable structure. In somecases, an endoprostheis provided herein is a stent. For example, a stentprovided herein can include plurality of struts arranged to form agenerally tubular structure that can be expanded or retracted between aplurality of different diameters. In some cases, an endoprosthesisprovided herein can consist of a magnesium alloy or magnesium alloycomposite provided herein. In some cases, an endorposthesis providedherein can include one or more additional materials. For example, insome cases an endoprosthesis provided herein can include a coating. Insome cases, a coating provided on an endoprosthesis provided herein hasa thickness of between 5 nm and 20 nm. In some cases, a coating providedon an endoprosthesis provided herein includes titanium oxide, aluminumoxide, or a combination thereof. In some cases, a coating provided on anendoprosthesis provided herein includes a therapeutic agent.

One advantage of an endoprosthesis including a bioerodible magnesiumalloy having a microstructure or composite structure provided herein isthat the resulting endoprosthesis' mechanical properties and degradationrate can be tailored to maintain desired mechanical properties over adesired period of time and an optimal bioerosion rate. A bioerodiblemagnesium alloy having a microstructure provided herein can haveimproved ductility as compared to similar alloys having differentmicrostructures. In some cases, ceramic nanoparticles provided in acomposite provided herein can simplify a grain refinement procedure bypinching grain boundaries and inhibiting grain growth during one or morehigh-strain processes.

The details of one or more embodiments are set forth in the accompanyingdrawings and the description below. Other features, objects, andadvantages will be apparent from the description and drawings, and fromthe claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a perspective view of a representative stent.

FIG. 2 depicts an exemplary arrangement for fabricating amagnesium-alloy ceramic-nanoparticle composite.

FIG. 3 depicts an exemplary Equal-Channel Angular Extrusion die.

FIGS. 4A-4D show SBF Immersion results for stents. FIG. 4A depicts apost-test SEM WE43 element stent as received. FIG. 4B depicts apost-test SEM AZNd element sent as received. FIG. 4C depicts a post-testSEM AZNd element stent nominally expanded to 3.0 mm. FIG. 4D depicts apost-test SEM AZNd element sent overexpanded beyond 3.0 mm.

FIG. 5 depicts the mass loss per area over time for a WE43 elementstent, a AZNd element stent, and a L1c element stent in a ratsubcutaneous model.

DETAILED DESCRIPTION

A stent 20, shown in FIG. 1, is an example of an endoprosthesis. Stent20 includes a pattern of interconnected struts forming a structure thatcontacts a body lumen wall to maintain the patency of the body lumen.For example, stent 20 can have the form of a tubular member defined by aplurality of bands 22 and a plurality of connectors 24 that extendbetween and connect adjacent bands. During use, bands 22 can be expandedfrom an initial, small diameter to a larger diameter to contact stent 20against a wall of a vessel, thereby maintaining the patency of thevessel. Connectors 24 can provide stent 20 with flexibility andconformability that allow the stent to adapt to the contours of thevessel. Other examples of endoprostheses include covered stents andstent-grafts.

At least one strut of stent 20 can be adapted to erode underphysiological conditions. In some cases, stent 20 is fully bioerodible.Stent 20 can include a composite of a matrix including a bioerodiblemagnesium alloy including a plurality of rare earth metals. In somecases, the rare earth metals can include scandium (Sc), yttrium (Y),lanthanum (La), neodymium (Nd), gadolinium (Gd), terbium (Tb),dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), and/orlutetium (Lu). In some cases, the bioerodible magnesium alloy caninclude zirconium (Zr), calcium (Ca), zinc (Zn), and/or indium (In). Insome cases, a bioerodible magnesium alloy provided herein can include atleast 5.5 weight percent in sum of one or more elements selected fromthe group consisting of selected from the group consisting of Ho, Er,Lu, Tb and Tm. In some cases, a bioerodible magnesium alloy providedherein can include at least 2.0 weight percent in sum of one or moreelements selected from the group consisting of selected from the groupconsisting of Y, Nd and Gd. In some cases, a bioerodible magnesium alloyprovided herein can include at least 3.0 weight percent in sum of one ormore elements selected from the group consisting of selected from thegroup consisting of Y, Nd and Gd.

A bioerodible magnesium alloy formulation provided herein can have a Ycontent of between 0-10.0 weight percent. In some cases, a bioerodiblemagnesium alloy formulation provided herein can have a Y content ofbetween 1.0-6.0 weight percent. In some cases, a bioerodible magnesiumalloy formulation provided herein can have a Y content of between3.0-4.0 weight percent.

A bioerodible magnesium alloy formulation provided herein can have a Ndcontent of between 0-4.5 weight percent. In some cases, a bioerodiblemagnesium alloy formulation provided herein can have a Nd content ofbetween 0.05-2.5 weight percent.

A bioerodible magnesium alloy formulation provided herein can have a Gdcontent of between 0-9 weight percent. In some cases, a bioerodiblemagnesium alloy formulation provided herein can have a Gd content ofbetween 0-4.0 weight percent.

A bioerodible magnesium alloy formulation provided herein can have a Dycontent of between 0-8.0 weight percent. In some cases, a bioerodiblemagnesium alloy formulation provided herein can have a Dy content ofbetween 0-6.0 weight percent. In some cases, a bioerodible magnesiumalloy formulation provided herein can have a Dy content of between 0-4.0weight percent.

In some cases, a bioerodible magnesium alloy formulation provided hereincan have a Ho content of between 0-19.0 weight percent. In some cases, abioerodible magnesium alloy formulation provided herein can have a Hocontent of between 4.0-15.0 weight percent. In some cases, a bioerodiblemagnesium alloy formulation provided herein can have a Ho content ofbetween 6.0-14.0 weight percent.

A bioerodible magnesium alloy formulation provided herein can have a Ercontent of between 0-23.0 weight percent. In some cases, a bioerodiblemagnesium alloy formulation provided herein can have a Er content ofbetween 4.0-15.0 weight percent. In some cases, a bioerodible magnesiumalloy formulation provided herein can have a Er content of between6.0-14.0 weight percent.

A bioerodible magnesium alloy formulation provided herein can have a Lucontent of between 0-25.0 weight percent. In some cases, a bioerodiblemagnesium alloy formulation provided herein can have a Lu content ofbetween 4.0-15.0 weight percent. In some cases, a bioerodible magnesiumalloy formulation provided herein can have a Lu content of between6.0-14.0 weight percent.

A bioerodible magnesium alloy formulation provided herein can have a Tmand/or Tb content of between 0-21.0 weight percent. In some cases, abioerodible magnesium alloy formulation provided herein can have a Tmand/or Tb content of between 4.0-15.0 weight percent. In some cases, abioerodible magnesium alloy formulation provided herein can have a Tmand/or Tb content of between 6.0-12.0 weight percent.

A bioerodible magnesium alloy formulation provided herein can totalcontent of Ho, Er, Lu, Tb and Tm of more than 5.5 weight percent in sum.In some cases, a bioerodible magnesium alloy formulation provided hereincan total content of Ho, Er, Lu, Tb and Tm of between 6.5-25.0 weightpercent. In some cases, a bioerodible magnesium alloy formulationprovided herein can total content of Ho, Er, Lu, Tb and Tm of between7.0-15.0 weight percent.

A bioerodible magnesium alloy formulation provided herein can have a Sccontent of between 0-15 weight percent.

The solubility of rare earth metals in magnesium varies considerably,and the addition of the amounts of rare earth metals provided herein canresult secondary phase precipitates. In some cases, a volume of coarsesecondary phase precipitates present would be primarily related to theNd content, due to its low solid solubility in magnesium. Processingtechniques provided herein, however, can create a microstructure wherethe coarse secondary phase precipitates have an average longestdimension of 2.0 microns or less and be primarily centered in the grainboundaries of magnesium-rich solid solution alpha-phase grains.Processing techniques provided herein, however, can create amicrostructure where the coarse secondary phase precipitates have anaverage longest dimension of 1.0 microns or less and be primarilycentered in the grain boundaries of magnesium-rich solid solutionalpha-phase grains. Processing techniques provided herein, however, cancreate a microstructure where the coarse secondary phase precipitateshave an average longest dimension of 500 nanometers or less and beprimarily centered in the grain boundaries of magnesium-rich solidsolution alpha-phase grains. In some cases, processing techniquesprovided herein can create a microstructure where at least 80% of coarsesecondary phase precipitates have a longest dimension of 2.0 microns orless and be primarily centered in the grain boundaries of magnesium-richsolid solution alpha-phase grains. In some cases, processing techniquesprovided herein can create a microstructure where at least 90% of coarsesecondary phase precipitates have a longest dimension of 2.0 microns orless and be primarily centered in the grain boundaries of magnesium-richsolid solution alpha-phase grains. In some cases, processing techniquesprovided herein can create a microstructure where at least 95% of coarsesecondary phase precipitates have a longest dimension of 2.0 microns orless and be primarily centered in the grain boundaries of magnesium-richsolid solution alpha-phase grains. In some cases, processing techniquesprovided herein can create a microstructure where at least 80% of coarsesecondary phase precipitates have a longest dimension of 1.0 microns orless and be primarily centered in the grain boundaries of magnesium-richsolid solution alpha-phase grains. In some cases, processing techniquesprovided herein can create a microstructure where at least 90% of coarsesecondary phase precipitates have a longest dimension of 1.0 microns orless and be primarily centered in the grain boundaries of magnesium-richsolid solution alpha-phase grains. In some cases, processing techniquesprovided herein can create a microstructure where at least 95% of coarsesecondary phase precipitates have a longest dimension of 1.0 microns orless and be primarily centered in the grain boundaries of magnesium-richsolid solution alpha-phase grains. In some cases, processing techniquesprovided herein can create a microstructure where at least 80% of coarsesecondary phase precipitates have a longest dimension of 500 nanometersor less and be primarily centered in the grain boundaries ofmagnesium-rich solid solution alpha-phase grains. In some cases,processing techniques provided herein can create a microstructure whereat least 90% of coarse secondary phase precipitates have a longestdimension of 500 nanometers or less and be primarily centered in thegrain boundaries of magnesium-rich solid solution alpha-phase grains. Insome cases, processing techniques provided herein can create amicrostructure where at least 95% of coarse secondary phase precipitateshave a longest dimension of 500 nanometers or less and be primarilycentered in the grain boundaries of magnesium-rich solid solutionalpha-phase grains. Processing techniques provided herein can createrelatively equiaxed magnesium-rich solid solution alpha-phase grainshaving an average grain diameter of less than or equal to 15 microns(longest dimension in a metallography cross-section plane). Processingtechniques provided herein can create relatively equiaxed magnesium-richsolid solution alpha-phase grains having an average grain diameter ofless than or equal to 10 microns (longest dimension in a metallographycross-section plane). Processing techniques provided herein can createrelatively equiaxed magnesium-rich solid solution alpha-phase grainshaving an average grain diameter of less than or equal to 5 microns(longest dimension in a metallography cross-section plane).

A bioerodible magnesium alloy formulation provided herein can have a Zrcontent of between 0.1-1.5 weight percent. In some cases, a bioerodiblemagnesium alloy formulation provided herein can have a Zr content ofbetween 0.2-0.6 weight percent. In some cases, a bioerodible magnesiumalloy formulation provided herein can have a Zr content of between0.2-0.4 weight percent.

A bioerodible magnesium alloy formulation provided herein can have a Cacontent of between 0-2.0 weight percent. In some cases, a bioerodiblemagnesium alloy formulation provided herein can have a Ca content ofbetween 0-1.0 weight percent. In some cases, a bioerodible magnesiumalloy formulation provided herein can have a Ca content of between0.1-0.8 weight percent.

A bioerodible magnesium alloy formulation provided herein can have a Zncontent of between 0-1.5 weight percent. In some cases, a bioerodiblemagnesium alloy formulation provided herein can have a Zn content ofbetween 0-0.5 weight percent. In some cases, a bioerodible magnesiumalloy formulation provided herein can have a Zn content of between0.1-0.3 weight percent.

A bioerodible magnesium alloy formulation provided herein can have a Incontent of between 0-12.0 weight percent. In some cases, a bioerodiblemagnesium alloy formulation provided herein can have a In content ofbetween 0-2.5 weight percent. In some cases, a bioerodible magnesiumalloy formulation provided herein can have a In content of between0.0-0.8 weight percent.

A bioerodible magnesium alloy formulation provided herein can, in somecases, have a total content of In, Zr, Ca and Zn in the Mg alloy in therange of 0.2-2.0 weight percent. In some cases, a bioerodible magnesiumalloy formulation provided herein can have a total content of In, Zr, Caand Zn in the Mg alloy in the range of 0.2-0.8 weight percent.

A bioerodible magnesium alloy formulation provided herein can, in somecases, have a total content of impurities of less than 0.3 weightpercent. In some cases, a bioerodible magnesium alloy formulationprovided herein can have a total content of impurities of less than 0.2weight percent. In some cases, a bioerodible magnesium alloy formulationprovided herein can have a maximum of 0.05 weight percent of each of Fe,Si, Cu, Mn, and Ag. In some cases, a bioerodible magnesium alloyformulation provided herein can have a maximum of 0.006 weight percentof Ni. In some cases, a bioerodible magnesium alloy formulation providedherein can have a maximum of 0.15 weight percent of each of La, Ce, Pr,Sm, Eu and Yb. In some cases, a bioerodible magnesium alloy formulationprovided herein can have a maximum of 0.1 weight percent of each of La,Ce, Pr, Sm, Eu and Yb.

The secondary-phase precipitates can have an average longest dimensionof 500 nanometers or less can be formed in bioerodible magnesium alloysprovided herein using processes provided herein. Secondary-phaseprecipitates can be predominantly located in grain boundaries ratherthan within grains (e.g., >50% of the combined area of second-phaseprecipitates are on grain boundaries in a given prepared metallographycross-section plane examined at 100-300× magnification). For example, amajority of the second-phase precipitates (i.e., the secondary-phase)can located are located in grain boundaries rather than within theMg-rich solid solution-phase grains. Magnesium alloys having themicrostructures provided herein can have improved mechanical propertiessuitable for endoprostheses, such as stents. In some cases, ceramicnanoparticles can be added to the alloy during the process and can alsohave an average longest dimension of 500 nanometers or less and bepredominantly located in grain boundaries rather than within grains.

Although magnesium and magnesium alloys have been explored as candidatematerials for bioerodible endoprostheses in the past, the mechanicalproperties of magnesium and magnesium alloys have presented certaindifficulties that make the use of a bioerodible magnesium metal or alloyin certain endoprostheses, such as stents, impractical. In particular,magnesium alloys can have a limited ductility due to a lack of availableslip planes in the Hexagonal Close Packed (HCP) crystal lattice. Slipplanes can accommodate plastic deformation. Limited ductility cancomplicate certain uses that rely upon plastic deformation. For example,limited ductility can make stent crimping and stent expansion morecomplex due to an increased probability of stent fractures during theseplastic deformations. Moreover, magnesium alloys typically have a lowertensile strength than iron alloys (such as stainless steel alloys).Bioerodible magnesium alloys having a microstructure provided herein,however, can have improved ductility and tensile strength.

Certain magnesium alloys were tested in order to identify magnesiumalloys having suitable bioerosion rates and ductility. For example, L1cand WE43 (described in Table I below) were prototyped and tested asstents, but found to have a bioerosion rate that was too fast whensubjected to in-vivo and in-vitro testing. It is possible, however, thata L1c and/or WE43 alloy having a microstructure provided herein wouldhave a suitable bioerodison rate for an endoprosthesis.

TABLE I Other Alloy Ex. Zn Zr Mn Y Ca Ag Fe Elements Mg L1c 2.87 ≦0.020.15 — 0.22 0.10 0.0036 — Balance WE43 0.20 0.36 0.13 4.16 — — — 3.8091.35

Certain modifications of the AZ80 alloy (see Table II below) have alsobeen developed in an attempt to find a magnesium alloy having superiorcorrosion resistance to that of L1c, but also having sufficientductility. Although initial mechanical testing of these AZ80 modifiedalloys showed an improvement in the mechanical and corrosion propertiesas compared to L1c, AZ80 modified alloy stents cracked and fractured ata nominal expanded diameter. A stent made from AZNd alloy using aprocess described herein, however, demonstrated good mechanicalproperties, as discussed below.

TABLE II Alloy Example Al Zn Mn Y Nd La Mg AZ80 7.5 0.5 0.2 — — —Balance AZNd 7.3 0.6 0.1 — 0.7 — Balance AZY 7.4 0.6 0.1 0.5 — — BalanceAZNdY 7.0 0.6 0.2 0.5 0.6 — Balance AZM 7.3 0.6 0.4 — — — Balance AZL7.0 0.5 0.2 — — 1.2 Balance AE82 8.0 0.5 0.2 0.5 1.0 — Balance

An analysis of the stents identified the presence of large extrinsicintermetallic particles, e.g., oxide inclusions and coarse Mg solidsolution grain sizes, which are deleterious to ductility. Low materialductility can result in stent cracking, especially in balloon-expandablestents that are crimped onto a balloon catheter, guided through a longtortuous path, and expanded to fill the diameter of the artery.

Microstructures and processes provided herein can eliminate this rootcause of low material ductility and stent cracking by having lowerextrinsic inclusion content (or at least much smaller inclusions), andstent material with refined Mg solid solution grain size to randomizegrain texture, produce additional slip systems through grain sizerefinement and raise the activation energy needed to initiate a crackdue to the presence of a tortuous grain boundary network.Microstructures and processes provided herein can be tailored tomanifest sufficient ductility in a balloon-expandable stent design suchthat the Mg alloy stent would allow the stent to be crimped onto aballoon catheter, wiggled through a long tortuous path, and expanded tofill the diameter of the artery without fracturing.

A microstructure of material can be at least partially dependent on theprocessing techniques and parameters. The grains (i.e., crystals) of amagnesium alloy can align themselves with their basal planes parallel tothe direction of the processing material flow, which can result indifferent mechanical properties in the direction of flow as compared tothe a direction perpendicular to the direction of flow. In the case ofextruding stent tubing including the alloys of Table II, the resultingtube may have a strong preferred crystal orientation, aligning the basalplanes in the extrusion direction, which produces increased ductility inthe extrusion direction of the tubing, but less ductility in a directionperpendicular to the extrusion direction. The expansion of a stent,however, relies upon the material having suitable ductility in alldirections. A strong grain texture with an unfavorable loading along thec-crystal axis components of the grains causes twinning and voidnucleation under lower strains. The twinning with void nucleation can bethe initiation of an eventual material failure. Stent tube extrusion mayalso produce a randomized crystal structure with no preferredorientation, which produces more isotropic mechanical properties, butstill suffers from the ductility issues discussed above.

Microstructures provided herein can provide superior ductility and othermechanical properties in multiple directions. Grain boundaries aredecorated with precipitates and/or ceramic nanoparticles.Microstructures provided herein can be characterized in a number ofways. In some cases, the microstructures provided herein, when viewed ata 500× using x-ray diffraction, have no more than 3% by area filled withintermetallic (“IM”) particles. In some case, the microstructuresprovided herein have no more than 2% by area filled with IM particles.In some cases, a maximum IM particle dimension will be 30 microns orless. In some cases, a maximum IM particle dimension will be 20 micronsor less, 10 microns or less, 5 microns or less, or 1 micron or less.

In some cases, the grain boundaries can be decorated with ceramicnanoparticles. Ceramic nanoparticles can pinch grain boundaries and/orimpede grain growth during processing of the material, which can resultin a fine grain microstructure of the magnesium alloy. The fine grainmicrostructure of the magnesium alloy can increase strength andductility of the material. In some case, the microstructures providedherein have at least 0.5% by area filled with ceramic particles. In somecase, the microstructures provided herein have at least 1.0% by areafilled with ceramic particles. In some case, the microstructuresprovided herein have between 0.5% and 5% by area filled with ceramicparticles. In some case, the microstructures provided herein havebetween 1.0% and 3% by area filled with ceramic particles. In some case,the microstructures provided herein have about 1.5% by area filled withceramic particles.

Ceramic nanoparticles provided in a composite provided herein can haveany appropriate dimensions. In some cases, ceramic nanoparticles used ina composite provided herein have an average largest diameter of between0.5 nanometers and 500 nanometers, between 1.0 nanometer and 200nanometers, between 5 nanometers and 100 nanometers, between 10nanometers and 100 nanometers, between 25 nanometers and 75 nanometers,or between 40 nanometers and 60 nanometers. In some cases, a maximumceramic nanoparticle dimension will be 5 micron or less. In some cases,a maximum ceramic nanoparticle dimension will be 1 micron or less, 500nanometers or less, 5 microns or less, or 200 nanometers or less.

Ceramic nanoparticles provided in a composite provided herein caninclude any suitable ceramic material. In some cases, ceramicnanoparticles provided herein are insoluble in a magnesium alloy used ina composite provided herein. In some cases, ceramic nanoparticles caninclude one or more of the following ceramic materials: TiC, TiO₂ Si₃N₄,AlN, Al₂O₃, CeO₂, Boron Nitride, B₄C, and Y₂O₃. In some cases, ceramicnanoparticles used in a composite provided herein include a radiopaqueceramic material. In some cases, ceramic nanoparticles used in acomposite provided herein can have an electro-motive force within 50% ofthe electro-motive force of magnesium. In some cases, ceramicnanoparticles used in a composite provided herein can have anelectro-motive force within 25% of the electro-motive force ofmagnesium. In some cases, ceramic nanoparticles used in a compositeprovided herein can have an electro-motive force within 10% of theelectro-motive force of magnesium. In some cases, ceramic nanoparticlesused in a composite provided herein can have an electro-motive forcewithin 5% of the electro-motive force of magnesium. Suitable ceramicnanoparticles are available from SkySpring Nanomaterials, Houston Tex.

The microstructures provided herein can include equiaxed Mg-rich solidsolution-phase grains with second-phase precipitates and/or ceramicnanoparticles located within smooth and equiaxed alpha-phase-grainboundaries. In some cases, the equiaxed equiaxed Mg-rich solidsolution-phase grains have an average grain size of 20 microns or less,15 microns or less, 10 microns or less, 7.5 microns or less, 5 micronsor less, 4 microns or less, 3 microns or less, 2 microns or less, or 1microns or less. In some cases, the equiaxed Mg-rich solidsolution-phase grains have an average grain size of between 0.1 micronsand 10 microns, of between 0.5 microns and 5 microns, or between 1micron and 4 microns. In some cases, at least 90% by volume of thesecondary phase particles can be found along alpha phase grainboundaries. In some cases, the average secondary phase individualparticle diameter or longest dimension is 1 microns or less, 500nanometers or less, 300 nanometers or less, 200 nanometers or less, 100nanometers or less, 75 nanometers or less, 50 nanometers or less, or 25nanometers or less. In some cases, the average secondary phaseindividual particle diameter or longest dimension is between 0.1nanometers and 1 micron, between 0.5 nanometer and 500 nanometers,between 5 nanometers and 300 nanometers, between 10 nanometers and 200nanometers, between 20 nanometers and 100 nanometers, between 25nanometers and 75 nanometers, or between 40 nanometers and 60nanometers. The microstructure provided herein can have a reduced numberof twin bands. In some cases, less than 15% of the alpha grains willhave twin bands. In some cases, the number of alpha grains having twinbands can be less than 10%, less than 5%, or less than 1% when the stentis cut and crimped.

Microstructures provided herein can have enhanced ductility. Themicrostructures provided herein can overcome the basal plane alignmentby randomizing grain orientations and result in isotropic mechanicalproperties. Finer grains also yield increased grain boundary areas,which can provide more grain boundary slip. Refinement of precipitatediameter may also allow additional grain boundary slip. Moreover, ahomogenous dispersion of secondary-phase precipitates and/or ceramicnanoparticles along the grain boundaries can improve strength andcorrosion resistance. In some cases, the precipitates and/or ceramicnanoparticles can be substantially centered on the grain boundary but belarger than the width of the grain boundary.

For example, a tubular body (e.g., stent tubing material) made from abioerodible magnesium alloy formulation provided herein can be made by aprocess as described below. The bioerodible magnesium alloy can include,for example, 3.5 weight percent Y, 1.0 weight percent Nd, 2.0 weightpercent Gd, 0.5 weight percent Dy, 8 weight percent Ho, 3.0 weightpercent Tm, 3.0 weight percent Tb, 0.5 weight percent Zr, and a balanceof Magnesium. The bioerodible magnesium alloy formulation providedherein can have an elastic modulus of between 39 and 200 GPa, a 0.2%Offset Yield Strength of between 150 and 600 MPa, an ultimate tensilestrength of between 225 and 600 MPa, and/or a tensile reduction in area(RIA) of between 30% and 80%. In some cases, stent tubing materialprovided herein can have a tensile RIA of between 45% and 80%. In somecases, stent tubing material provided herein can maintain its initialelastic modulus, Yield Strength, ultimate tensile strength, and atensile RIA within +/−10% after storage of the tubing for 180 days at atemperature of between 20° C. and 25° C. and a relative humidity of lessthan 30%.

Table III

Bioerodible magnesium alloys having a microstructure provided herein canbe polished to have a smooth surface finish. In some cases, anendoprosthesis provided herein can have a surface including abioerodible magnesium alloy having a surface roughness R_(a) of lessthan 0.5 microns, less than 0.4 microns, less than 0.3 microns, lessthan 0.2 microns, less than 0.1 microns, or less than 0.05 microns.Bioerodible magnesium alloys having microstructure provided herein canhave improved corrosion resistance, which can provide a slowerbioerosion rate. A stent body of a bioerodible magnesium alloy having amicrostructure provided herein can have an in-vitro corrosionpenetration rate of less than 200 μm/year after a period of 28 days ofcontinuous immersion in non-flowing, agitated Simulated Body Fluid(agitated at 60 rpm) at 37° C. where the Simulated Body Fluid (“SBF”) ispresent in an amount of at least 10 times the initial volume of thestent material. The ingredients of SBF, which are added to water, areshown in Table III.

TABLE III SBF Ingredients Chemical Mass/Volume NaCl 5.403 g NaHCO₃ 0.504g Na₂CO₃ 0.426 g KCl 0.225 g K₂HPO₄•3H₂O 0.230 g MgCl₂•6H₂O 0.311 g 0.2MNaOH 100 mL HEPES 17.892 g CaCl₂ 0.293 g Na₂SO₄ 0.072 g

Microstructures provided herein can be formed by using the followingprocess steps: (a) mix elements to form a molten magnesium alloy (andoptionally add ceramic nanoparticles); (b) cooling the molten magnesiumalloy to form a ingot or billet; (c) solution treating a billet tosolutionize any intermetallic precipitates formed during solidificationof the alloy; (d) controlled cooling after solutionizing to form adistribution of fine discontinuous or continuous precipitates alonggrain boundaries; and (e) thermomechanical deformation of the materialafter or during cooling to refine the Mg-rich solid solution grain sizeand produce a substantially equiaxed grain morphology.

For example, an ingot or billet can be formed or machined into a solidor hollow rod, homogenized, subjected to a high-strain process to refinethe microstructure, and then shaped or machined into stent tubing fromwhich the stent is manufactured into final dimensions (e.g., thedimensions of a stent body). In some cases, a billet or ingot providedherein can be formed into an endoprosthesis that does not normallyundergo expansion, for example vascular closing plugs or embolicalmaterial (e.g., microbeads used to close off unwanted vascularstructures or cancerous tissue).

Ceramic nanoparticles can optionally be dispersed within a moltenmagnesium alloy using any suitable method. FIG. 2 depicts an exemplaryarrangement 200 for introducing ceramic nanoparticles 210 into a moltenmagnesium alloy 220. Magnesium metal and one or more alloyingconstituents (e.g., aluminum) can be introduced to a steel crucible 202within a resistance furnace 204. In some case, magnesium is alloyed withalloying elements prior to introduction to steel crucible 202 orresistance furnace 204. In some cases, magnesium is alloyed withalloying elements in steel crucible 202 before, after, or concurrentlywith an addition of ceramic nanoparticles. A protection gas 206 can beused to prevent unwanted reactions or exposure to oxygen. In some cases,energy can be used to prevent ceramic nanoparticles from agglomeratingduring the mixing process. For example, an ultrasonic probe 230 can beplaced within steel crucible 202 to impart ultrasonic energy to themixture. The mixture can then be cooled to form a billet or ingot.

Billets can be made using any suitable process. A billet can have adiameter of between 2 centimeters and 1 meter. In some cases, an ingotof a desired bioerodible magnesium alloy can be made by conventionalmelting and solidification in a mold (liquid casting), thixomolding(semi-solid processing) or powder metallurgy (solid-processing). Theingot can then be machined to the desired dimensions of the billet whichwill serve as the feedstock for subsequent processing and shaping. Insome cases, a billet can be formed without additional machining process.To form an endoprosthesis (e.g., a stent body) out of a billet, thebillet can be converted into a rod or hollow tube having a smallerdiameter. In some cases, the ingot or billet is converted into a rod orhollow tube after the ingot or billet is homogenized. In some cases, therod or hollow tube can have an outer diameter of between 1 centimeterand 6 centimeters. In the case of a stent, a hollow tube provided hereincan then be further reduced in diameter and cut to form individual stentbodies, including fenestrations between stent struts. In some cases, thestent struts can have a width to thickness ratio of less than 1.2. Insome cases, the thickness of the hollow tube and the stent struts can bebetween 80 microns and 160 microns.

An ingot or billet, in some cases, can be made by thixomolding theelements of the bioerodible magnesium alloy (and optionally ceramicnanoparticles). Thixomolding involves mixing solid constituents into aportion of the composition that is in a liquid phase and then coolingthe mixture to reach a fully solid state. Thixomolding can reduce thenumber and size of brittle inter-metallic (IM) particles in the alloy.For example, thixomolding can use a machine similar to an injectionmold. Room temperature magnesium alloy chips, chips of the other alloyconstituents, and optionally ceramic nanoparticles can be fed into aheated barrel through a volumetric feeder. The heated barrel can befilled with an inert gas (e.g., argon) to prevent oxidation of themagnesium chips. A screw feeder located inside the barrel can feed themagnesium chips and other alloy constituents forward as they are heatedinto a semi-solid temperature range. For example, the mixture can beheated to a temperature of about 442° C. The screw rotation can providea shearing force that can further reduce the size of IM particles. Onceenough slurry has accumulated, the screw can move forward to inject theslurry into a steel die having the shape of an ingot or billet.

An ingot or billet, in some cases, can be made by combining the elementsof the bioerodible magnesium alloy using powder metallurgy. Powdermetallurgy involves the solid-state sintering of elemental orpre-alloyed powder particles and optionally ceramic nanoparticles. Usingfine powders in a sintering process can avoid the formation of coarse IMparticles. For example, fine powders of magnesium, other alloyingconstituents, and optionally ceramic nanoparticles can be blended into ahomogenous mixture, pressed into a desired shape (e.g., the shape of theingot or billet), and heated while compressed to bond the powderstogether. Sintering can be conducted in an inert atmosphere (e.g.,argon) to avoid oxidation of the magnesium.

An ingot or billet including all of the desired elements of abioerodible magnesium alloy and the optional ceramic nanoparticles canbe homogenized to reduce elemental concentration gradients. The ingot orbillet can be homogenized by heating the ingot or billet to an elevatedtemperature below the liquidus temperature of the bioerodible magnesiumalloy and holding the ingot or billet at that temperature for period oftime sufficient to allow elemental diffusion within the ingot or billetto reduce elemental concentration gradients within the ingot or billet.

Homogenizing the ingot or billet can solutionize intermetallic (IM)second-phase precipitate particles, because the homogenizationtemperature is in excess of the phase boundary (solvus temperature)between the high-temperature single, solid phase (alpha) and two-phasefield boundary on the Mg—Al phase diagram. A follow-on solutioningtreatment at the same or similar position within the phase diagram canbe used in some cases to refine the precipitate structure. For example,a follow-on solutioning treatment can be used if the homogenizationtreatment cooling was not controlled sufficiently to tailor thesecond-phase precipitate size and location. In some cases, the ingot orbillet is cooled rapidly after holding the ingot or billet at theelevated temperature in order to form relatively fine IM second-phaseprecipitates. For example, the ingot or billet can be cooled from theelevated hold temperature via force gas cooling or liquid quenching. Theingot or billet can be homogenized in an inert atmosphere (e.g., in anargon atmosphere) or open atmosphere so long as surface oxides areremoved. In some cases, the ingot or billet provided herein can behomogenized at a temperature of between 400° C. and 450° C. In somecases, the ingot or billet is held at a temperature of between 400° C.and 450° C. for at least 2 hours, at least 3 hours, or at least 4 hours.In some cases, the hold time at an elevated temperature is between 4hours and 24 hours. For example, a bioerodible magnesium alloy ingothaving a diameter of about 15 centimeters can be heated to a temperatureof 440° C. for 6 hours to homogenize the ingot, followed by quenchingthe ingot in a cooled argon gas stream.

An ingot or billet can be subjected to one or more high-strain processesto refine the microstructure into a microstructure provided herein. Insome cases, the high-strain process(es) can include one or moreequal-channel high-strain processes. Equal-channel high-strain processesinclude Equal-Channel Angular Extrusion (“ECAE”) and Equal-ChannelAngular Pressing (“ECAP”). ECAE is an extrusion process that producessignificant deformation strain without reducing the cross sectional areaof the piece. ECAE can be accomplished by extruding the alloy (e.g., abillet of the alloy) around a corner. For example, a billet of abioerodible magnesium alloy provided herein can be forced through achannel having a 90 degree angle. The cross section of the channel canbe equal on entry and exit. The complex deformation of the metal as itflows around the corner can produce very high strains. In some cases, aningot can be machined into a billet having the exact dimensions of thechannel of an ECAE die prior to an ECAE process. Because the crosssection can remain the same, the billet can be extruded multiple timeswith each pass introducing additional strain. With each ECAE process,the orientation of the billet can be changed to introduce strain alongdifferent planes. In some cases, an ECAE die can include multiple bends.For example, FIG. 3 depict an example of an ECAE die.

The ingot or billet provided herein can be extruded through one or moreECEA dies (e.g., as depicted in FIG. 3) at temperatures lower than ahomogenization temperature. Multiple equal-channel high-strainextrusions can be performed at subsequently lower temperatures. Theequal-channel high-strain processes can yield a fine grain size withfine secondary-phase precipitates (i.e., IM particles) that areprimarily located along the grain boundaries. The optional ceramicparticles can also become located along the grain boundaries ifincluded. In some cases, the dynamic recrystallization of the grainrefinement caused by successive equal-channel high-strain extrusions atdeclining temperatures can introduce more strain into the material andresult in finer grain sizes as compared to cold working and annealingsteps. In some cases, an ingot or billet is subjected to at least twoECAE processes at two different sequentially-lower temperatures. In somecases, an ingot or billet is subjected to at least three ECAE processesat different sequentially-lower temperatures.

For example, a billet including a magnesium-aluminum alloy can beprocessed through two ECAE processes, with the first ECAE processoccurring at a higher temperature than the second ECAE process. Eachprocess can occur through a simple ECAE die have a single 90° corner,such as that depicted in FIG. 3. The first ECAE process can be conductedat a temperature of between 250° C. and 400° C. to allow good diffusionof rare earth elements to the grain boundaries. The first ECAE processcan result in a microstructure having an average grain diameter of 15microns or less. A second ECAE process can be done at a temperature ofbetween 150° C. and 300° C. The second ECAE process can further refinethe grain sizes and avoid coarsening.

In the ECAE process shown in FIG. 3, an ingot or prior-worked billet 30a is extruded through a channel 31 a including two channel portions 32a, 33 a of substantially identical cross-sectional areas having therespective centerlines thereof disposed at an angle 35 a. As shown,angle 35 a can be about 90°. In some cases, angle 35 a can be between45° and 170°, between 50° and 160°, between 60° and 135°, between 70°and 120°, between 80° and 100°, or between 85° and 95°. Billet 30 a canhave any appropriate cross section and machined to provide a snug fitinto entry channel portion 32 a. In some cases, billet 30 a can have acircular cross sectional shape. A ram 38 a can force billet 30 a throughchannel 31 a using an appropriate extrusion ram pressure. The strainimposed on billet 30 a is a function of angle 35 a.

Composites provided can, in some cases, be made by sintering powders ofmetal alloy and ceramic nanoparticles together. In some cases, powdermetallurgy techniques can be used to form a composite provided herein.

The billet can be formed into a rod or hollow tube having a reducedouter diameter after one or more high-strain processes. Tube or roddrawing from the billet can occur in multiple steps, with optionalintermediate and final annealing steps, to reduce the diameter. Thedrawing and annealing processes can be controlled to preserve themicrostructure formed in the one or more high-strain processes. In somecases, the material is annealed at a temperature of less than 300° C. Insome cases, the material is annealed at a temperature of between 150° C.and 300° C., between 150° C. and 250° C., or between 150° C. and 200° C.Annealing steps can be used to allow recovery with limitedrecrystallization and avoid grain growth or changes in precipitatevolume fraction and morphology. Annealing steps can also maintain ahomogenous dispersion of secondary-phase precipitates at the grainboundaries.

Individual stent bodies can then be cut, including cutting fenestrationsbetween stent struts, using any suitable technique. For example, thefenestrations can be cut using a laser.

A coating can be applied over a bioerodible magnesium alloy or compositeof an endoprosthesis provided herein. For example, a stent providedherein can include a stent body formed of a bioerodible magnesium alloyincluding a microstructure or composite provided herein and a coatingoverlying the surface of the stent body. A coating can slow or delay theinitial degradation of the bioerodible magnesium alloy or composite uponplacement within a physiological environment by serving as a temporarybarrier between the magnesium alloy and the environment. For example,delaying the bioerosion processes can allow the body passageway to healand a stent to become endothelialized (surrounded by tissues cells ofthe lumen wall) before the strength of the stent is reduced to a pointwhere the stent fails under the loads associated with residing within abody lumen (e.g., within a blood vessel). When an endothelialized stentfragments, the segments of the stent can be contained by the lumen walltissue and are thus less likely to be released into the blood stream.Endothelialization can also block the oxygen-rich turbulent flow of theblood stream from contacting the endoprosthesis, thus further reducingthe erosion rate of the endoprosthesis. In some case, a stent providedherein can include a coating that includes titanium oxide, aluminumoxide, or a combination thereof. Examples of suitable coatings can befound in U.S. Patent Application Publication No. 2012/0059455, which ishereby incorporate by reference in its entirety, particularly thesections describing coatings formed by atomic layer deposition.

In some cases, an endoprosthesis provided herein can include a sprayedlayer of magnesium fluoride nanoparticles. Magnesium fluoridesuspensions can be applied to an endoprosthesis provided herein using asuspension plasma spray (SPS) process, which can deliver nearlymonodisperse nanoparticles in a gram scale yield to provide a protectivemagnesium fluoride layer. The SPS process can use a Sulzer Metco TriplexII torch attached on an ABB industrial robot.

The stent can optionally include a therapeutic agent. In some cases, thecoating can include a therapeutic agent. In some cases, the coating caninclude a polymer (e.g., a bioerodible polymer). For example, adrug-eluting polymeric coating can be applied to the stent body providedherein. In some cases, a stent provided herein can be essentiallypolymer-free (allowing for the presence of any small amounts ofpolymeric materials that may have been introduced incidentally duringthe manufacturing process such that someone of ordinary skill in the artwould nevertheless consider the coating to be free of any polymericmaterial). The therapeutic agent may be any pharmaceutically acceptableagent (such as a drug), a biomolecule, a small molecule, or cells.Exemplary drugs include anti-proliferative agents such as paclitaxel,sirolimus (rapamycin), tacrolimus, everolimus, biolimus, andzotarolimus. Exemplary biomolecules include peptides, polypeptides andproteins; antibodies; oligonucleotides; nucleic acids such as double orsingle stranded DNA (including naked and cDNA), RNA, antisense nucleicacids such as antisense DNA and RNA, small interfering RNA (siRNA), andribozymes; genes; carbohydrates; angiogenic factors including growthfactors; cell cycle inhibitors; and anti-restenosis agents. Exemplarysmall molecules include hormones, nucleotides, amino acids, sugars,lipids, and compounds have a molecular weight of less than 100 kD.Exemplary cells include stem cells, progenitor cells, endothelial cells,adult cardiomyocytes, and smooth muscle cells.

A stent provided herein can include one or more imaging markers. Imagingmarkers can assist a physician with the placement of the stent. Imagingmarkers can be radiopaque marks to permit X-ray visualization of thestent.

Stent 20 can be configured for vascular, e.g., coronary and peripheralvasculature or non-vascular lumens. For example, it can be configuredfor use in the esophagus or the prostate. Other lumens include biliarylumens, hepatic lumens, pancreatic lumens, and urethral lumens.

Stent 20 can be of a desired shape and size (e.g., coronary stents,aortic stents, peripheral vascular stents, gastrointestinal stents,urology stents, tracheal/bronchial stents, and neurology stents).Depending on the application, the stent can have a diameter of between,e.g., about 1 mm to about 46 mm. In certain embodiments, a coronarystent can have an expanded diameter of from about 2 mm to about 6 mm. Insome cases, a peripheral stent can have an expanded diameter of fromabout 4 mm to about 24 mm. In certain embodiments, a gastrointestinaland/or urology stent can have an expanded diameter of from about 6 mm toabout 30 mm. In some cases, a neurology stent can have an expandeddiameter of from about 1 mm to about 12 mm. An abdominal aortic aneurysm(AAA) stent and a thoracic aortic aneurysm (TAA) stent can have adiameter from about 20 mm to about 46 mm. The stent can beballoon-expandable, self-expandable, or a combination of both (e.g., seeU.S. Pat. No. 6,290,721).

Non-limiting examples of additional endoprostheses that can include abioerodible magnesium alloy including a microstructure provided hereininclude stent grafts, heart valves, and artificial hearts. Suchendoprostheses are implanted or otherwise used in body structures,cavities, or lumens such as the vasculature, gastrointestinal tract,lymphatic system, abdomen, peritoneum, airways, esophagus, trachea,colon, rectum, biliary tract, urinary tract, prostate, brain, spine,lung, liver, heart, skeletal muscle, kidney, bladder, intestines,stomach, pancreas, ovary, uterus, cartilage, eye, bone, joints, and thelike. In some cases, an endoprosthesis can include a biodegradablescaffold for the lymphatic system.

EXAMPLE

A sample AZNd alloy having the elements listed in Table II was producedas discussed herein and extruded at 400° C. Samples of AZNd alloy weretested for expansion failures and compared to a control alloy L1c. Asshown in Table IV below, the AZNd alloy demonstrated suitable mechanicalproperties for a nominal expansion of 3.0 mm.

TABLE IV Mg Stent Design and Material Development and Testing MaterialTest Results L1c L1c L1c AZNd AZNd AZNd 3.0 mm ID 5/9 0/5 0/9 0/6 0/30/3 Deploy Fractures Overexpansion No Test 5/5 5/5 3/3 3/3 2/2 FracturesAve. Overexpansion No Test 3.97 4.36 4.22 3.63 3.69 OD (mm)

FIGS. 4A-4D show SBF Immersion results for stents. The stents wereimmersed in SBF for 54 hours. FIG. 4A depicts a post-test SEM WE43element stent as received. FIG. 4B depicts a post-test SEM AZNd elementsent as received. FIG. 4C depicts a post-test SEM AZNd element stentnominally expanded to 3.0 mm. FIG. 4D depicts a post-test SEM AZNdelement sent overexpanded beyond 3.0 mm. As shown, the AZNd elementstents had a more even and slower erosion rate as compared to the WE43element control. The AZNd element stent had an alpha grain size of about11 microns.

FIG. 5 depicts the mass loss per area over time for a WE43 sheet, a AZNdhypotube section, and a L1c hypotube section in a rat subcutaneousmodel. The AZNd alloy was produced as discussed herein and extruded at400° C. The AZNd hypotube section was placed in a rat in a PMMA cage for120 days. The WE43 sheet was placed in a PMMA cage for 45 days anddirect subcutaneous for 90 days. The L1c was placed in a PMMA cage for30 days and direct subcutaneous for 15 days. The data in FIG. 5 showsthe change in mass for the sample over time (after washing away salts).As shown in FIG. 5, during the initial degradation during days 0-45, theAZNd element stent had a slower degradation than the WE43 element stentby about 1.5 times followed by further slowing down.

All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference herein in their entirety.

Still further embodiments are within the scope of the following claims.

What is claimed is:
 1. A bioerodible endoprosthesis comprising: abioerodible magnesium alloy comprising: between 50 weight percent and 92weight percent magnesium, at least 5.5 weight percent in sum of one ormore elements selected from the group consisting of Ho, Er, Lu, Tb andTm; and at least 2.0 weight percent in sum of one or more elementsselected from the group consisting of Y, Nd and Gd; the bioerodiblemagnesium alloy having a microstructure comprising equiaxed Mg-richsolid solution phase grains having an average grain diameter of lessthan or equal to 15 microns; and continuous or discontinuoussecond-phase precipitates or ceramic nanoparticles in grain boundariesbetween the Mg-rich solid solution-phase grains, the second-phaseprecipitates or ceramic nanoparticles having an average longestdimension of 2.0 micron or less.
 2. The endoprosthesis of claim 1,wherein the second-phase precipitates or ceramic nanoparticles areprimarily centered upon the gran boundaries and do not extend into aMg-rich solid solution phase grain interior by more than 1 micron fromthe grain boundary when viewed at 200-500× magnification on ametallography plane.
 3. The endoprosthesis of claim 1, wherein theequiaxed Mg-rich solid solution phase grains have an average graindiameter of less than or equal to 1 micron and the second-phaseprecipitates or ceramic nanoparticles have an average longest dimensionof between 0.5 nanometer and 200 nanometers.
 4. The endoprosthesis ofclaim 1, wherein less than 50% of the equiaxed Mg-rich solidsolution-phase grains have twin bands.
 5. The endoprosthesis of claim 4,wherein less than 15% of the equiaxed Mg-rich solid solution-phasegrains have twin bands.
 6. The endoprosthesis of claim 1, wherein thebioerodible magnesium alloy includes secondary-phase precipitatesoutside the grain boundaries, wherein at least 50% of the total amountof secondary-phase precipitates are located in grain boundaries betweenthe equiaxed Mg-rich solid solution-phase grains.
 7. The endoprosthesisof claim 1, wherein the endoprosthesis comprises the ceramicnanoparticles and the ceramic nanoparticles are insoluble in thebioerodible magnesium alloy.
 8. The endoprosthesis of claim 7, whereinthe ceramic nanoparticles comprise a ceramic material selected from thegroup consisting of TiC, Si₃N₄, AlN, Al₂O₃, CeO₂, Boron Nitride, B₄C,Y₂O₃, and combinations thereof.
 9. The endoprosthesis of claim 1,wherein the alloy has an elastic modulus of between 39 GPa and 200 GPa,a 0.2% offset yield strength of between 150 MPa and 600 MPa, an ultimatetensile strength of between 250 MPa and 600 MPa, and a tensile reductionin area of at least 30%.
 10. The endoprosthesis of claim 1, wherein thebioerodible magnesium alloy comprises a Y content of between 0-10.0weight percent, a Nd content of between 0-4.5 weight percent, a Gdcontent of between 0-9 weight percent, and a Dy content of between 0-8.0weight percent.
 11. The endoprosthesis of claim 1, wherein thebioerodible magnesium alloy comprises a Ho content of between 4.0-15.0weight percent.
 12. The endoprosthesis of claim 1, wherein thebioerodible magnesium alloy comprises a Er content of between 4.0-15.0weight percent.
 13. The endoprosthesis of claim 1, wherein thebioerodible magnesium alloy comprises a Lu content of between 4.0-15.0weight percent.
 14. The endoprosthesis of claim 1, wherein thebioerodible magnesium alloy comprises a Tm and/or Tb content of between4.0-15.0 weight percent.
 15. The endoprosthesis of claim 1, wherein thebioerodible magnesium alloy consist of: Y: 0-10.0 weight percent; Nd:0-4.5 weight percent; Gd: 0-9.0 weight percent; Dy: 0-8.0 weightpercent; Ho: 0-19.0 weight percent; Er: 0-23.0 weight percent; Lu:0-25.0 weight percent; Tm: 0-21.0 weight percent; Tb: 0-21.0 weightpercent; Zr: 0.1-1.5 weight percent; Ca: 0-2.0 weight percent; Zn: 0-1.5weight percent; In: 0-12.0 weight percent; Sc: 0-15.0 weight percent;incidental impurities up to a total of 0.3 weight percent; and thebalance being magnesium and under the condition that a total content ofHo, Er, Lu, Tb and Tm is more than 5.5 weight percent; a total contentof Y, Nd and Gd is more than 2.0 weight percent; and a total content ofall alloy compounds except magnesium is more than 8.5 weight percent.16. The endoprosthesis of claim 1, wherein the endoprosthesis is a stentcomprising a plurality of struts, wherein the struts have a width tothickness ratio of less than 1.2.
 17. The endoprosthesis of claim 1,wherein the endoprosthesis has a surface finish having an R_(a) surfaceroughness of less than 0.2 microns.